Crucial role of hyaluronan derived from macrophages in neointimal formation after vascular injury.

• Project/Area Number: 26860550
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Cardiovascular medicine
• Research Institution: Shinshu University
• Principal Investigator: KASHIMA Yuichiro 信州大学, 学術研究院医学系(医学部附属病院), 助教 (70545722)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000); Fiscal Year 2016: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2015: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2014: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: ヒアルロン酸 / 新生内膜肥厚 / マクロファージ / 血管障害モデル / 動脈硬化

Outline of Final Research Achievements

Hyaluronan (HA) is a primary component of the extracellular matrix of cells, and it is involved in the pathogenesis of atherosclerosis. HA was found to be expressed in neointimal lesions after wire-mediated vascular injury in mice. Inhibition of HA synthesis using 4-methylumbelliferone markedly inhibited neointimal formation after injury. In vitro experiments revealed that low-molecular-weight HA (LMW-HA) induced macrophages activation, including migration and production of inflammatory cytokines, and reactive oxygen species (ROS). The migration of macrophages were mediated by the CD44/RhoA. Because HA synthase 2 (HAS2) is predominantly expressed in injured arteries, we generated cTg mice that overexpress the murine HAS2 gene specifically in macrophages (cHAS2/CreLys mice) and showed that HA overexpression markedly enhanced neointimal formation after cuff-mediated vascular injury. Macrophages-derived HA promotes neointimal formation after vascular injury.

Research Products

• [Journal Article] Characterization of cardiac oxidative stress levels in patients with atrial fibrillation. (2016)
  • Author(s): Okada A, Kashima Y, Tomita T, Takeuchi T, Aizawa K, Takahashi M, Ikeda U.
  • Journal Title: Heart Vessels. Volume: ３１ Pages: 80-87
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Assessment of lipophilic vs. hydrophilic statin therapy in acute myocardial infarction – ALPS-AMI study. (2015)
  • Author(s): Izawa A, Kashima Y, Miura T, Ebisawa S, Kitabayashi H, Yamamoto H, Sakurai S, Kagoshima M, Tomita T, Miyashita Y, Koyama J, Ikeda U; ALPS-AMI Investigators.
  • Journal Title: Circ J. Volume: 63 Pages: 161-168
  • NAID: 40020311883
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] A 2-year follow-up of oxidative stress levels in patients with ST-segment elevation myocardial infarction: a subanalysis of the ALPS-AMI study. (2015)
  • Author(s): Abe N, Kashima Y, Izawa A, Motoki H, Ebisawa S, Miyashita Y, Imamura H, Ikeda U.
  • Journal Title: Angiology. Volume: ６６ Pages: 271-277
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Characterization of cardiac oxidative stress levels in patients with atrial fibrillation. (2015)
  • Author(s): Okada A, Kashima Y, Tomita T, Takeuchi T, Aizawa K, Takahashi M, Ikeda U.
  • Journal Title: Heart Vessels Volume: in press
  • Peer Reviewed
• [Journal Article] A 2-year follow-up of oxidative stress levels in patients with ST-segment elevation myocardial infarction: a subanalysis of the ALPS-AMI study. (2015)
  • Author(s): Abe N, Kashima Y, Izawa A, Motoki H, Ebisawa S, Miyashita Y, Imamura H, Ikeda U.
  • Journal Title: Angiology Volume: 66(3) Issue: 3 Pages: 271-277
  • DOI: 10.1177/0003319714525656
  • Peer Reviewed / Open Access
• [Journal Article] Assessment of Lipophilic vs. Hydrophilic Statin Therapy in Acute Myocardial Infarction (2014)
  • Author(s): Izawa A, Kashima Y, Miura T, Ebisawa S, Kitabayashi H, Yamamoto H, Sakurai S, Kagoshima M, Tomita T, Miyashita Y, Koyama J, Ikeda U.
  • Journal Title: Circulation Journal Volume: 79 Issue: 1 Pages: 161-168
  • DOI: 10.1253/circj.CJ-14-0877
  • NAID: 130004704019
  • ISSN: 1346-9843, 1347-4820
  • Peer Reviewed / Open Access
• [Presentation] Crucial role of hyaluronan in neointimal formation after vascular injury. (2016)
  • Author(s): Kashim Yuichiro, Masafumi Takahashi, Uichi Ikeda
  • Organizer: American Heart Association Scientific Session
  • Place of Presentation: 米国ニューオーリンズ
  • Year and Date: 2016-11-12
  • Int'l Joint Research